In all well-characterized epidemics there are individuals in the population that respond differently to the infectious agent. Although resistance to infection is the most common variable phenotype, variation in disease outcomes has also been observed. Epidemiologic studies have shown that inherited factors are involved in the risk of mortality to infectious agents. The HIV-1 epidemic presents a critical challenge to apply current genetic techniques to the study of host genetic variation for infection and susceptibility to infection. This problem is confounded in the studies of HIV-1 by the rapid rate of evolution of the virus. The CKR5 gene serves as a secondary receptor on CD4+ T lymphocytes for certain strains of human immunodeficiency virus. The CKR5 gene was mapped to human chromosome 3p21, and a 32 base pair deletion allele (CKR5delta32) was identified that is present at a frequency of approximately 0.10 in the Caucasian population. An examination of 1955 patients included among six well-characterized AIDS cohort studies revealed that 18 deletion homozygotes occur exclusively among 612 exposed HIV-1-antibody negative individuals (2.8%) and not in 1343 HIV-1-infected individuals. CKR5 deletion heterozygotes (+/delta32) were significantly elevated among patients that survive HIV-1 infection for more than 10 years, in some cases twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes. The CKR5delta32 deletion may act as a recessive restriction gene against HIV-1 infection and exerts a dominant phenotype of delaying progression to AIDS among infected patients. In addition, we have identified five other alterations in the CKR5 gene, including four missense alterations in conserved residues, and an amino acid deletion. These alterations should further add to the understanding of the role of CKR5 in HIV infection and disease progression.